RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia

Leukemia-associated chimeric oncoproteins often act as transcriptional repressors, targeting promoters of master genes involved in hematopoiesis. We show that CRABPI (encoding cellular retinoic acid binding protein I) is a target of PLZF, which is fused to RARalpha by the t(11;17)(q23;q21) transloca...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-11, Vol.104 (47), p.18694-18699
Main Authors: Guidez, Fabien, Parks, Sarah, Wong, Henna, Jovanovic, Jelena V, Mays, Ashley, Gilkes, Amanda F, Mills, Kenneth I, Guillemin, Marie-Claude, Hobbs, Robin M, Pandolfi, Pier Paolo, de Thé, Hugues, Solomon, Ellen, Grimwade, David
Format: Article
Language:English
Subjects:
Base Sequence
Binding Sites
Cell Line
Chromatin - genetics
Chromosomes, Human, Pair 11 - genetics
Chromosomes, Human, Pair 17 - genetics
Disease Progression
DNA Methylation
Drug Resistance, Neoplasm - drug effects
Gene Expression Regulation, Neoplastic
Humans
Kruppel-Like Transcription Factors - metabolism
Leukemia, Promyelocytic, Acute - genetics
Leukemia, Promyelocytic, Acute - metabolism
Leukemia, Promyelocytic, Acute - pathology
Molecular Sequence Data
Promyelocytic Leukemia Zinc Finger Protein
Receptors, Retinoic Acid - genetics
Receptors, Retinoic Acid - metabolism
Retinoic Acid Receptor alpha
Retinoids - pharmacology
Up-Regulation
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Summary:Leukemia-associated chimeric oncoproteins often act as transcriptional repressors, targeting promoters of master genes involved in hematopoiesis. We show that CRABPI (encoding cellular retinoic acid binding protein I) is a target of PLZF, which is fused to RARalpha by the t(11;17)(q23;q21) translocation associated with retinoic acid (RA)-resistant acute promyelocytic leukemia (APL). PLZF represses the CRABPI locus through propagation of chromatin condensation from a remote intronic binding element culminating in silencing of the promoter. Although the canonical, PLZF-RARalpha oncoprotein has no impact on PLZF-mediated repression, the reciprocal translocation product RARalpha-PLZF binds to this remote binding site, recruiting p300, inducing promoter hypomethylation and CRABPI gene up-regulation. In line with these observations, RA-resistant murine PLZF/RARalpha+RARalpha/PLZF APL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RARalpha APL. RARalpha-PLZF confers RA resistance to a retinoid-sensitive acute myeloid leukemia (AML) cell line in a CRABPI-dependent fashion. This study supports an active role for PLZF and RARalpha-PLZF in leukemogenesis, identifies up-regulation of CRABPI as a mechanism contributing to retinoid resistance, and reveals the ability of the reciprocal fusion gene products to mediate distinct epigenetic effects contributing to the leukemic phenotype.
ISSN:1091-6490